The development of HIV protease inhibitors was the most successful structure-based drug design effort to date. This effort was based on extensive investigations of the conformational and functional properties of the enzyme. HIV protease inhibitors, in combination with inhibitors of reverse transcriptase, are very effective in suppressing HIV blood concentrations, often to undetectable levels. Unfortunately, exposure to protease inhibitors often leads to mutations in the protease gene. In particular, the combined substitutions L63P, V82T, and I84V cause a reduction in the binding affinity of all 5 of the HIV protease inhibitors presently prescribed. In the present study, X-ray crystal structures of this multi-drug resistant variant of HIV protease, in complex with the 5 inhibitors presently approved by the FDA will be solved. These three dimensional structures, in combination with the results of kinetics experiments, will allow an analysis of the mechanisms by which these mutations affect drug binding affinities and enzyme activity. Finally, the technique of substrate phage display will be employed as a means of identifying and optimizing protease cleavage sites or binders to this drug resistant variant. The combined results of these studies will provide drug leads for the design of new and better HIV protease inhibitors.